The present application is for new funding of a program project grant on the Pathogenesis and Prevention of Autoimmune Diabetes. The purpose of this funding is to allow four investigators who have worked together in the past to continue to do in the future. The program consists of four projects supported by three cores. the projects are as follows: Project 1: C.A. Janeway, PI. This project focuses on CD8 T cells that can transfer acute diabetes to NOD mice. These CD8 cloned T cells lines enter the islets in three hours and cause diabetes in all mice tested. We will study their homing, construct a TCR transgenic mouse, and identify the beta cell antigen they detect. Project 2: R.A. Flavell, PI. This project is designed to analyze tolerance in models using normal and NOD transgenic mice, to ask if there is a generalized defecting tolerance in the NOD mice, and to determine its mechanism. Project 3: A.C. Hayday, PI. This project will examine the role of the autoantigen glutamic acid decarboxylase (GAD) in NOD mice. We have observed strong promotion of insultis and some increase in diabetes in these mice. The aim of the project is to study this acceleration, using TCR transgenes specific for GAD. Project 4: RS.Sherwin, PI. This project is mainly focused on the characterization of insulin-specific protective T cell clones. Their mechanism of action and their development will be characterized using TCR transgenics, hopefully leading to a vaccine. The four projects are supported by three core facilities: Core A, Administrative Core, C. Janeway PI; Core B, Animal core, Fs. Wong, PI; Core C, Islet Isolation and Imunohistopathology Core, M. Solimena, PI.